chr4-42893406-C-T

Position:

chr4-42893406-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_001080476.3(GRXCR1):c.140C>T(p.Ala47Val) variant causes a missense change. The variant allele was found at a frequency of 0.0823 in 1,613,614 control chromosomes in the GnomAD database, including 9,540 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.085 ( 952 hom., cov: 32)

Exomes 𝑓: 0.082 ( 8588 hom. )

Consequence

GRXCR1
NM_001080476.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.76

Variant links:

Genes affected

GRXCR1 (HGNC:31673): (glutaredoxin and cysteine rich domain containing 1) This gene is one of 60 loci associated with autosomal-recessive nonsyndromic hearing impairment. This gene encodes a protein which contains GRX-like domains; these domains play a role in the S-glutathionylation of proteins and may be involved in actin organization in hair cells. [provided by RefSeq, Sep 2010]

GRXCR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Glutaredoxin domain-containing cysteine-rich protein 1 (size 289) in uniprot entity GRCR1_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_001080476.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0016952157).

BP6

Variant 4-42893406-C-T is Benign according to our data. Variant chr4-42893406-C-T is described in ClinVar as [Benign]. Clinvar id is 43886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-42893406-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRXCR1	NM_001080476.3 linkuse as main transcript	c.140C>T	p.Ala47Val	missense_variant	1/4	ENST00000399770.3	NP_001073945.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRXCR1	ENST00000399770.3 linkuse as main transcript	c.140C>T	p.Ala47Val	missense_variant	1/4	1	NM_001080476.3	ENSP00000382670	P1

Frequencies

GnomAD3 genomes

AF:

0.0846

AC:

12856

AN:

151934

Hom.:

955

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0598

Gnomad AMI

AF:

0.240

Gnomad AMR

AF:

0.163

Gnomad ASJ

AF:

0.0464

Gnomad EAS

AF:

0.334

Gnomad SAS

AF:

0.257

Gnomad FIN

AF:

0.0308

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0593

Gnomad OTH

AF:

0.0823

GnomAD3 exomes

AF:

0.123

AC:

30647

AN:

249146

Hom.:

3292

AF XY:

0.125

AC XY:

16869

AN XY:

135160

show subpopulations

Gnomad AFR exome

AF:

0.0556

Gnomad AMR exome

AF:

0.206

Gnomad ASJ exome

AF:

0.0416

Gnomad EAS exome

AF:

0.347

Gnomad SAS exome

AF:

0.256

Gnomad FIN exome

AF:

0.0308

Gnomad NFE exome

AF:

0.0613

Gnomad OTH exome

AF:

0.0979

GnomAD4 exome

AF:

0.0821

AC:

119993

AN:

1461562

Hom.:

8588

Cov.:

AF XY:

0.0866

AC XY:

62949

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.0584

Gnomad4 AMR exome

AF:

0.206

Gnomad4 ASJ exome

AF:

0.0427

Gnomad4 EAS exome

AF:

0.319

Gnomad4 SAS exome

AF:

0.252

Gnomad4 FIN exome

AF:

0.0320

Gnomad4 NFE exome

AF:

0.0587

Gnomad4 OTH exome

AF:

0.0933

GnomAD4 genome

AF:

0.0847

AC:

12875

AN:

152052

Hom.:

952

Cov.:

AF XY:

0.0903

AC XY:

6710

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0598

Gnomad4 AMR

AF:

0.164

Gnomad4 ASJ

AF:

0.0464

Gnomad4 EAS

AF:

0.334

Gnomad4 SAS

AF:

0.257

Gnomad4 FIN

AF:

0.0308

Gnomad4 NFE

AF:

0.0593

Gnomad4 OTH

AF:

0.0843

Alfa

AF:

0.0744

Hom.:

1105

Bravo

AF:

0.0912

TwinsUK

AF:

0.0561

AC:

208

ALSPAC

AF:

0.0669

AC:

258

ESP6500AA

AF:

0.0537

AC:

213

ESP6500EA

AF:

0.0584

AC:

488

ExAC

AF:

0.120

AC:

14456

Asia WGS

AF:

0.264

AC:

914

AN:

3476

EpiCase

AF:

0.0598

EpiControl

AF:

0.0616

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ala47Val in Exon 01 of GRXCR1: This variant is not expected to have clinical sig nificance because it has been identified in 5.7% (386/6772) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs57655409). -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 25

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.075

Eigen

Benign

-0.021

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.90

MutationTaster

Benign

0.28

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.89

REVEL

Benign

0.035

Sift

Benign

0.18

Sift4G

Benign

0.54

Polyphen

0.075

Vest4

0.21

MPC

0.046

ClinPred

0.0056

GERP RS

5.7

Varity_R

0.14

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over